Ticagrerol intravenous preparation used to treat Gram-positive bacteremia

Abstract

This invention relates to an aqueous ticagrelol solution for intravenous administration for use in the treatment of Gram-positive bacterial infections in the bloodstream of patients. This invention is advantageous for further improving the efficacy of treating bacteremia, particularly MSSA and MRSA bacteremia and bacteremia-associated thrombocytopenia.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical compositions and medical uses of pharmaceutical compositions. The present invention is beneficial in that it provides a ticagrelor intravenous solution with excellent solubility and storage stability of ticagrelor suitable for use in the treatment of patients suffering from Gram-positive bacterial bloodstream infection (bacteremia). The present invention improves the effectiveness of treatment and helps save lives.

Background Art

[0002] Ticagrelor is a well-known active ingredient, and its chemical name is (1S,2S,3R,5S)-3-{7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(propylthio)-3H-(1,2,3)triazolo(4,5-D)pyrimidin-3-yl}-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. Ticagrelor has the following chemical structure.

[0003] JPEG2026509786000001.jpg83145

[0004] Ticagrelor has established uses in the field of cardiology. It is used for the prevention of thrombotic events such as myocardial infarction and stroke in patients with acute coronary syndrome.

[0005] Recently, applications of ticagrelor other than for cardiac disease have been proposed. Lancelloti et al. reported that ticagrelor exhibits ex vivo antibacterial properties at concentrations far higher than those encountered in the treatment of cardiac disease (Non-Patent Literature 1) (JAMA Cardiol. 2019, 4(6):596-599). The minimum bactericidal concentrations were 20 micrograms / ml against methicillin-sensitive Staphylococcus aureus (MSSA), glycopeptide intermediate Staphylococcus aureus (GISA), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Streptococcus fecal (VRE), 30 micrograms / ml against methicillin-resistant Staphylococcus epidermidis (MRSE), and 40 micrograms / ml against Enterococcus and Staphylococcus agalactier.

[0006] Lancelotti and Oury disclose in [Patent Document 1] (International Publication No. WO2018046174) the use of triazolo(4,5-D)pyrimidine derivatives for the treatment of bacterial infections. Ticagrelol is part of a long list of defined triazolo(4,5-D)pyrimidine derivatives ([Figure 1]). It is disclosed that the triazolo(4,5-D)pyrimidine derivatives of this invention can exert their effects through various formulations. However, there is no disclosure of specific ticagrelol compositions or the use of ticagrelol in the treatment of bloodstream infections.

[0007] Ulloa et al. reported the first experimental use of ticagrelol in a single human patient in the treatment of a bacterial infection caused by Staphylococcus aureus (Non-Patent Literature 2) (J Infect Dis. 2021, 224(9):1566-1569). Ticagrelol tablets 90 mg were administered orally twice daily starting from day 5, in addition to antibiotic treatment with cefazolin and ertapenem. The patient took ticagrelol tablets for a total of 3 months and was hospitalized for 35 days.

[0008] While these results are very promising, the use of tablets may not be accepted in routine clinical practice, as some countries have guidelines that recommend the use of intravenous formulations for the treatment of bacteremia, particularly in cases of deep bacterial infections that cannot be surgically removed (complicated bacteremia). Tablets and other oral administration methods have the disadvantage of limited bioavailability. The oral bioavailability of ticagrelol is 36% (30-42% confidence interval), with significant individual variation (Non-patent Literature 3) (Teng and Maya, J Drug Assess. 2014, 3(1):43-). Therefore, prescription improvements are needed, especially in emergencies and life-threatening situations.

[0009] It is generally known that intravenous administration acts faster than oral administration (shorter half-life), has 100% bioavailability, and exhibits low variability. A ticagrelol formulation suitable for intravenous administration, preferably one that is readily available, would be beneficial. On the other hand, ticagrelol is notoriously difficult to handle. Its active ingredient is easily degraded when exposed to light, heat, and oxygen. Furthermore, its limited solubility poses a significant challenge in the development of pharmaceutical formulations. Ticagrelol has low solubility in aqueous media and is pH-independent. This property of not ionizing within the physiological pH range makes the development of liquid formulations particularly difficult. Yaye et al. (Non-Patent Literature 4 (J Pharm Biomed Anal. 2015; 105:74-83)) studied the degradation of ticagrelol when exposed to heat, pH, peroxides, and light. They identified numerous degradation products from DP1 to DP9, suggesting that this molecule is highly susceptible to degradation.

[0010] Ticagrerol is marketed as a tablet. It is sold under the brand name Brilinta (registered trademark) in the United States and Brilique (registered trademark) in the EU, in 60mg and 90mg tablets. Ticagrerol is not marketed as a liquid.

[0011] The product description for Brilique 60 mg or 90 mg film-coated tablets (Brilique INN-ticagrelol) states that for patients who cannot swallow tablets, the tablets can be crushed and mixed with water for immediate administration. Alternatively, the above mixture can be administered to the stomach via a nasogastric tube. The drawback of this formulation is that it is not readily available to patients and must be prepared immediately before administration. This formulation lacks long-term storage stability, and the tablet particles settle if left standing, making it unsuitable for intravenous administration. Furthermore, this formulation is not sterile.

[0012] Sigfridsson et al. (Non-Patent Literature 5) (J Pharm Sci. 2011, 100(6):2194-2202) have published a composition based on ticagrelor nanoparticles for obtaining a nanosuspension, and a composition based on polyvinylpyrrolidone, disodium aerosol AOT, and 5% mannitol for stabilizing the active ingredient. This aerosol AOT is thought to correspond to sodium dioctyl sulfosuccinate. This nanosuspension is reported to have stability for at least 10 months, but it has also been reported that particle aggregation and precipitation tend to occur during storage. Therefore, samples need to be sonicated before intravenous administration. This is cumbersome for pharmaceutical use and also carries safety risks. This formulation is not suitable for hospital use, especially in situations requiring acute treatment.

[0013] In the same paper by Sigfridsson et al., it was also reported that the concentration of ticagrel in phosphate buffer at pH 7.4 decreased after one month under normal laboratory conditions (light and temperature).

[0014] Na et al. (Non-Patent Literature 6 (Int J Nanomedicine. 2019, 14:1193-1212)) are studying a self-microemulsifying drug delivery system (SMEDDS) for oral administration to overcome barriers related to the solubility of ticagrelol. They are investigating the solubility of ticagrelol in oily and hydrophilic additives. To obtain an emulsion, they selected a surfactant combination of Capmul MCM / CremophorEL / TranscutolP. However, oily substances and surfactants are considered unsuitable for use in intravenous formulations.

[0015] Teng and Maya reported a single intravenous administration of ticagrelor 15 mg to healthy volunteers (150 mL of ticagrelor infusion: 0.1 mg / mL administered at a rate of 300 mL / hour over 30 minutes) (Non-Patent Literature 7 (J Drug Assess. 2014, 3(1):43-50)). This study did not provide information on the composition or stability of ticagrelor. It was likely newly prepared to compare the pharmacokinetics of oral and intravenous administration, but its use in patients has not been reported.

[0016] Considering the points above, there remains a need for intravenous ticagrelol formulations for use in the bloodstream treatment of patients suffering from Gram-positive bacterial infections. [Prior art documents] [Patent Documents]

[0017] [Patent Document 1] International Publication No. WO2018046174 [Non-patent literature]

[0018] [Non-Patent Document 1] JAMA Cardiol. 2019, 4(6):596-599 [Non-Patent Document 2] J Infect Dis. 2021, 224(9):1566-1569

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Summary of the Invention

Problems to be Solved by the Invention

[0019] The object of the present invention is to solve at least one or more of the above problems. In particular, the object of the present invention is to provide an intravenous formulation of ticagrelor for use in the treatment of gram-positive bacteremia. The intravenous formulation of ticagrelor needs to be easily accessible to patients, and the formulation preferably uses components that are acceptable to regulatory authorities (e.g., within the limits of the FDA's Inactive Ingredient Guide - IIG) in order to enable market introduction and supply to patients.

Means for Solving the Problems

[0020] According to a first aspect of the present invention, the present invention provides a ticagrelor pharmaceutical composition for use in the treatment of a patient requiring treatment for gram-positive bacteremia by administering a ticagrelor pharmaceutical composition having a therapeutically effective concentration, wherein the ticagrelor pharmaceutical composition is an aqueous solution of ticagrelor, has storage stability of at least 3 months at 25°C and a relative humidity of 60% or at 40°C and a relative humidity of 75%, and the administration is by intravenous administration either by injection or by infusion.

[0021] For use in the treatment of Gram-positive bacteremia infections there is available an intravenous administration composition of ticagrelol having an appropriate solubility of ticagrelol and with suppressed degradability, which has the advantage that 100% bioavailability is obtained by intravenous administration, making it easier to adjust the dosage and enabling administration even when the patient is unconscious. This intravenous preparation is advantageous for the treatment of deep bacterial infections that cannot be surgically removed.

[0022] Preferably, the above ticagrelol pharmaceutical composition has a pH of 5.5 to 9.0 and an osmotic pressure of 300 to 900 mOsm / kg.

[0023] Preferably, the above ticagrelol pharmaceutical composition contains a water-soluble inclusion complex in which ticagrelol is included in cyclodextrin, and preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0024] Preferably, no organic co-solvent is included (excluded).

[0025] Preferably, the ticagrelol pharmaceutical composition contains 1 to 15 mg / ml of ticagrelol and 15 to 40% w / w of cyclodextrin.

[0026] Preferably, the ticagrelol pharmaceutical composition has a volume of 1 to 15 ml in the case of injection administration and a volume of 10 to 50 ml in the case of short-term drip infusion administration for up to 30 minutes.

[0027] Preferably, the ticagrelol pharmaceutical composition contains 0.10 to 14 mg / ml of ticagrelol and 20 to 100 mg / ml of cyclodextrin.

[0028] Preferably, the ticagrelol pharmaceutical composition has a volume of 25 to 1000 ml in the case of drip infusion administration for at least 30 minutes.

[0029] Preferably, Gram-positive bacteremia is caused by Staphylococcus, Streptococcus, or Enterococcus, preferably by Staphylococcus aureus, and more preferably by antibiotic-resistant bacterial infection. Most preferably, Gram-positive bacteremia is caused by methicillin-sensitive (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA).

[0030] Preferably, the patient is further administered an antibiotic selected from cefazolin, cephthaloline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, telavancin, trimethoprim-sulfamethoxazole, vancomycin, or a combination thereof.

[0031] Preferably, intravenous administration of ticagrelor should be initiated within 4 days of bacterial bloodstream infection.

[0032] Preferably, the dose of ticagrelol is adjusted according to the level of alpha-toxin produced by Gram-positive bacterial strains present in bloodstream infections.

[0033] Preferably, the patient's platelet count is 50,000 to 150,000 per microliter of blood (thrombocytopenia).

[0034] Preferably, the treatment further includes administering an effective amount of platelets for the treatment of thrombocytopenia.

[0035] Preferably, platelets are pretreated with ticagrelol.

[0036] In another embodiment, the present invention provides a container containing a ticagrelol pharmaceutical composition according to the first embodiment.

[0037] Preferably, the container is a plastic bag or a glass bottle.

[0038] In a further embodiment, the present invention provides a ready-to-use ticagrelol formulation for administration to patients requiring treatment of Gram-positive bacteremia by intravenous administration of a therapeutically effective concentration of pharmaceutical composition, which is administered intravenously by infusion.

[0039] Preferably, the ready-to-use ticagrelol preparation described above is a ready-to-use container containing 25 to 1000 ml of aqueous solution, 0.10 to 14 mg / ml of ticagrelol, and 20 to 100 mg / ml of cyclodextrin, preferably hydroxypropyl-β-cyclodextrin.

[0040] Immediately available intravenous formulations are particularly beneficial when used to treat severe bacteremia that can lead to life-threatening thrombocytopenia (loss of platelets). Furthermore, patients may be unconscious and unable to take tablets. [Modes for carrying out the invention]

[0041] Unless otherwise defined, all terms used in this description of the present invention (including technical and scientific terms) have meanings generally understood by those skilled in the art in the field to which the present invention relates. Furthermore, definitions of terms are included to better understand this description of the present invention.

[0042] In this specification, the following terms have the following meanings: "A," "an," and "the" refer to both singular and plural forms unless otherwise specified in the context. "A Surface (surfactant)" refers to, for example, one or more (surfactants).

[0043] In this specification, "about" used to refer to measurable values ​​such as parameters, quantities, and durations includes variations of ±10%, preferably ±5%, more preferably ±3%, even more preferably ±1%, and even more preferably ±0.1% of the stated value, insofar as it is appropriate for carrying out the described invention. However, it is clear that the values ​​to which the term "about" relates are also specifically described. As used herein, "include," "comprising," and "comprises" are synonymous with "contain," "containing," or "contains," and are broad or open terms that identify, for example, a component and the presence of additional, unnamed components, features, elements, parts, or steps that are well known in the art or described herein, and do not exclude them.

[0044] When specifying a numerical range using endpoints, the range includes not only the endpoint itself, but also all the numbers and fractions contained within that range.

[0045] As used herein, the term "%w / w" means the weight percentage of the component relative to the total weight of the composition.

[0046] Bacterial bloodstream infections (bacteremia) are known to be very difficult to treat (especially when caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA)). MRSA produces large amounts of alpha-toxin, which attacks platelets, preventing them from producing enough platelets to activate the immune system to fight bacterial infection. Furthermore, a large number of platelets may be damaged and lost (thrombocytopenia), which can lead to an increased risk of bleeding and life-threatening situations (Non-Patent Literature 8). [Non-Patent Document 8] Alhurayri et al. Toxins, 2021, 13(10):726

[0047] The standard treatment for bacterial infections in the bloodstream is antibiotic therapy. Intravenous antibiotics are used for bacteremia caused by hospital-acquired infections. Intravenous antibiotics have the advantage of 100% bioavailability compared to oral antibiotics and a faster onset of therapeutic effect. Intravenous antibiotics are particularly needed for treating bloodstream infections caused by bacterial sources that cannot be removed surgically and are difficult to reach.

[0048] Recently, ticagrelor tablets have been considered as a treatment for bacteremia infections, but their bioavailability is only 36%, and there are significant individual differences. Therefore, intravenous formulations are not currently commercially available. To date, development efforts have not been able to dissolve ticagrelor at a medically appropriate concentration. Furthermore, its limited storage stability makes it insufficient for transitioning from prepared formulations.

[0049] The present invention provides an aqueous solution of ticagrelol for intravenous administration. Aqueous solutions of ticagrelol suitable for use in the present invention are described in concurrently filed applications PCT / EP2022 / 063185 and PCT / EP2023 / 055736, which are incorporated herein by reference.

[0050] The ticagrelol aqueous solution used in this invention has sufficient storage stability and is suitable for commercialization. Without sufficient storage stability, it would be impossible to manufacture, package, store, transport, and use the solution for patient treatment. Sufficient storage stability to avoid having to prepare and use the solution as needed is considered to require at least 3 months of storage stability when measured under storage stability conditions of 25°C and 60% relative humidity or under accelerated storage stability conditions of 40°C and 70% relative humidity.

[0051] More preferably, the storage stability is at least 6 months. Even more preferably, it is 9 months or more, and most preferably 12 months or more. Sufficient stability of 6 months at 40°C and 75% RH corresponds to a storage period of 24 months at room temperature of 25°C.

[0052] In this specification, "storage stability" means that the total impurity concentration is less than 0.5%.

[0053] The above-mentioned ticagrelol aqueous solution can be advantageously used to treat Gram-positive bacteremia by intravenously administering an effective amount of ticagrelol aqueous solution to patients who require it. Intravenous administration is performed by injection or infusion, depending on the concentration of ticagrelol.

[0054] This invention provides a solution to the problem of treating Gram-positive bacteremia in an improved manner using ticagrelol.

[0055] In particular, the present invention provides a ticagrelol pharmaceutical composition for use in the treatment of patients who require treatment of Gram-positive bacteremia by administering a ticagrelol pharmaceutical composition at a therapeutically effective concentration, characterized in that the ticagrelol pharmaceutical composition is an aqueous solution of ticagrelol, has storage stability for at least 3 months at 25°C and 60% relative humidity or 40°C and 75% relative humidity, and is administered intravenously by either injection or drip infusion.

[0056] In this specification, the term "bacteremia" refers to a bacterial infection in the bloodstream.

[0057] In this specification, the term "Gram-positive bacteria" refers to bacteria that show a positive result in the Gram staining test. The Gram staining test is a test known to those skilled in the art, classifying bacteria according to the type of cell wall. Gram-positive bacteria absorb the crystal violet stain used in the test and appear purple when observed under a light microscope. This is because, during the decolorization stage of the test, the thick peptidoglycan layer of the bacterial cell wall retains the stain even after the stain has been washed away from the rest of the sample. Gram-negative bacteria, on the other hand, cannot retain the crystal violet stain after the decolorization stage. The alcohol used in this stage degrades the outer membrane of Gram-negative cells and promotes the porosity of the cell wall, making it impossible to retain the crystal violet stain. The peptidoglycan layer of Gram-negative bacteria is very thin and sandwiched between the inner cell membrane and the bacterial outer membrane, so it absorbs counterstains such as safranin and fuchsin and appears red or pink.

[0058] In preferred embodiments, bacteremia is caused by Staphylococcus, Streptococcus, or Enterococcus. Preferably, bacteremia is caused by Staphylococcus aureus. More preferably, bacteremia is an antibiotic-resistant bacterial infection caused by Gram-positive bacteria. Most preferably, bacteremia is caused by methicillin-sensitive (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA). MRSA bacteremia is known to be very difficult to treat. The mortality rate is at least 20%.

[0059] The patient is preferably a mammal, and more preferably a human.

[0060] The present invention is advantageous in that it provides a storage-stable liquid formulation of ticagrelor suitable for intravenous administration. Veins are tubes that form part of the blood circulation system in a patient's body, carrying blood and platelets (also called thrombocytes). In the treatment of bacteremia, using an intravenous liquid formulation improves the bioavailability of ticagrelor to platelets in the bloodstream, protecting them from bacterial attack. Since platelets play a vital role in the immune system, protecting platelets is considered important in preventing bloodstream infections caused by Gram-positive bacteria.

[0061] Preferably, the pH of the product is such that no pH adjustment is required before administration. The above ticagrelol aqueous solution preferably has a pH of 5.5 to 9.0, more preferably 6.0 to 8.5, even more preferably 6.5 to 8.0, and most preferably 6.8 to 7.8.

[0062] Preferably, the osmotic pressure of the product does not require adjustment before administration. The ticagrelol aqueous solution used in the present invention preferably has an osmotic pressure of 300-900 mOsm / kg, more preferably 400-850 mOsm / kg, and most preferably 450-800 mOsm / kg. An osmotic pressure of 300-900 mOsm / kg allows for intravenous administration without prior adjustment of the formulation. This osmotic pressure is suitable for direct intravenous administration of ticagrelol formulations in the treatment of bacteremia. These parameters are beneficial for compatibility with the patient's bloodstream.

[0063] In preferred embodiments, the ticagrelol pharmaceutical composition further comprises a buffer, preferably a phosphate buffer. More preferably, the ticagrelol aqueous solution used in the present invention contains 5 mM to 20 mM phosphate buffer. This buffer concentration has been found to be advantageous in obtaining the desired storage stability of the ticagrelol aqueous solution.

[0064] Ticagrelol in the composition of the present invention is solubilized using a solubilizing agent. Preferably, the solubilizing agent is cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. Cyclodextrin, in particular hydroxypropyl-β-cyclodextrin, has been shown to provide a water-soluble inclusion complex of ticagrelol.

[0065] An aqueous ticagrelol pharmaceutical solution according to one embodiment of the present invention preferably has a volume of 5 to 1000 ml. This volume covers a range of several types of intravenous administration, with small doses usually administered by bolus injection and large doses administered by infusion.

[0066] Aqueous ticagrelol solutions for intravenous administration are preferably free of other solvents or surfactants. In particular, they are free of cosolvents consisting of oil, ethanol, propylene glycol, and polyethylene glycol. They are also preferably free of polymers consisting of poloxamer, polyvinylpyrrolidone, or combinations thereof. The exclusion of polyethylene glycol is particularly advantageous because polyethylene glycol tends to form impurities during storage, especially when exposed to temperatures above 35°C.

[0067] In preferred embodiments, salts are removed from the aqueous ticagrelol solution for intravenous administration. Removing the salts is beneficial to avoid the possibility of ticagrelol salting out from the cyclodextrin inclusion complex.

[0068] Ticagrerol solution for injection or short-term intravenous infusion In preferred embodiments, ticagrelol is administered by injection or short-term intravenous infusion.

[0069] Preferably, an aqueous ticagrelol pharmaceutical solution used for injection or short-term intravenous administration according to one embodiment of the present invention contains 1 to 15 mg / ml of ticagrelol. More preferably, the solution contains 2 to 14 mg / ml of ticagrelol. Even more preferably, the solution contains 3 to 12 mg / ml of ticagrelol. Most preferably, the solution contains 5 to 10 mg / ml of ticagrelol.

[0070] Preferably, a composition according to one embodiment of the present invention contains 15-40% w / w of hydroxypropyl-β-cyclodextrin. The use of this amount of cyclodextrin is advantageous for solubilizing ticagrelol and providing a solution with sufficient storage stability.

[0071] The most preferred ticagrelol pharmaceutical composition contains 1 to 15 mg / ml of ticagrelol and 15 to 40% w / w cyclodextrin.

[0072] In preferred embodiments, the ticagrelol used in the preparation of the ticagrelol solution of the present invention has a D90 particle size of less than 10 micrometers, as measured using a Malvern mastersizer. A small particle size has been found to be beneficial for readily incorporating ticagrelol into cyclodextrin and imparting solubility.

[0073] Short-term infusions are for a maximum of 30 minutes, preferably 25 minutes, more preferably 20 minutes, and even more preferably 15 minutes.

[0074] Preferably, the ticagrelol pharmaceutical composition according to one embodiment of the present invention has a volume of 10 to 50 ml for administration by short-term infusion over a maximum of 30 minutes.

[0075] This ticagrelol concentration range is sufficient for the treatment of bacteremia via intravenous administration. If the concentration is too low, an unacceptably large dose will be required to obtain an effective amount. This could lead to prolonged and uncomfortable administration. If the concentration is too high, maintaining solubility and storage stability becomes difficult. Furthermore, dilution before use becomes necessary.

[0076] The solution provided above is faster-acting than tablets, has higher bioavailability, and can be administered to patients with difficulty swallowing or who are unconscious. Direct intravenous administration allows ticagrelol to come into direct contact with platelets. The dosage can be easily adjusted according to the toxin levels released by the target bacterial strain.

[0077] Preferably, the ticagreol aqueous composition used in the present invention is a solution containing the following components.

[0078] 5-15 mg / ml of ticagrelol, 15-40% w / w hydroxypropyl-β-cyclodextrin, 5 mM to 20 mM phosphate buffer, The pH is between 5.5 and 8.

[0079] The above composition is simple and easy to manufacture. Because the number of components is limited, the generation of impurities and by-products is reduced.

[0080] Unexpectedly, a 5% glucose solution was found to be a suitable diluent for diluting the concentrated aqueous solution of the ticagrelor-cyclodextrin inclusion complex described above. Other solutions tested did not yield a clear ticagrelor solution. This could pose a problem when mixed with antibiotic preparations. This problem was resolved by preparing an alternative intravenous ticagrelor solution suitable for infusion, as described below.

[0081] Ticagrerol solution for intravenous infusion Instead of injection or short-term infusion, intravenous administration of ticagrelol aqueous solution is performed by infusion over at least 30 minutes.

[0082] Preferably, the ticagrelol intravenous composition contains 0.10 to 14 mg / ml of ticagrelol and 20 to 100 mg / ml of cyclodextrin. Preferably, the cyclodextrin is hydroxypropyl-β-cyclodextrin. The selected amount of cyclodextrin is the amount necessary to solubilize ticagrelol in the selected volume of aqueous pharmaceutical solution.

[0083] Preferably, the pH of the ticagrelol aqueous pharmaceutical solution is 6.0 to 8.5, more preferably 6.5 to 8.0, even more preferably 6.8 to 7.8, and most preferably about 7.5.

[0084] Preferably, the aqueous ticagrelol solution contains ticagrelol in an amount of 0.1 to 10.0 mg / ml, more preferably 0.2 to 8 mg / ml, even more preferably 0.3 to 6.0 mg / ml, and most preferably 0.4 to 5.0 mg / ml or 0.5 to 2.0 mg / ml. In a preferred embodiment, ticagrelol is the only active ingredient present in the aqueous ticagrelol solution.

[0085] Preferably, the ticagrelol intravenous administration composition has a volume of 25 to 1000 ml, more preferably 50 to 750 ml, even more preferably 75 to 500 ml, and most preferably 100 to 250 ml.

[0086] Unexpectedly, ticagrelol was found to be soluble in aqueous media at dilution concentrations. This is significant in the pharmaceutical field for the treatment of ticagrelol-responsive diseases.

[0087] More preferably, the above-mentioned ticagrelol aqueous pharmaceutical solution has storage stability of at least 4, 5, 6, 12, 18, or 24 months when measured at 25°C and 60% relative humidity.

[0088] In some embodiments, the ticagrelol aqueous pharmaceutical solution contains a 5 w / v% glucose solution.

[0089] Preferably, the above composition contains 3,000 to 16,000 mg, more preferably 4,000 to 15,000 mg, even more preferably 5,000 to 10,000 mg, and most preferably 6,000 to 8,000 mg of cyclodextrin. The above cyclodextrin is preferably hydroxypropyl-β-cyclodextrin. Most preferably, the above cyclodextrin is (2-hydroxypropyl)-β-cyclodextrin.

[0090] Use as a pharmaceutical In a preferred embodiment, bacteremia is caused by Staphylococcus, Streptococcus, or Enterococcus. Staphylococcus, Streptococcus, and Enterococcus are all bacteria that can enter a patient's bloodstream and cause infection.

[0091] Preferably, the bacteremia is caused by Staphylococcus aureus, more preferably by an antibiotic-resistant bacterial infection, and most preferably by methicillin-sensitive (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA). Intravenous administration of ticagrelor into the bloodstream is particularly useful in the treatment of staphylococcal infections. This is thought to be caused by ticagrelor blocking receptors on platelets in the bloodstream. Otherwise, platelets would be attacked by alpha-toxin produced by Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus (MRSA). The intravenous route of administration provides a rapid response to severe systemic invasion and rapidly protects platelets from bacterial attack. The inventors believe this effect promotes platelet survival. This protective effect may reduce the onset and severity of thrombocytopenia in patients with bacteremia. It may also prevent the development of infectious (bacterial) endocarditis. Infectious (bacterial) endocarditis is an infection caused by bacteria that enter the bloodstream and settle on the inner wall of the heart or on the heart valves.

[0092] As used herein, the term "thrombocytopenia" refers to a lower-than-normal number of platelets (blood cells) in the blood. In bacterial bloodstream infections, patients may exhibit thrombocytopenia due to bacterial attack. The platelet count in a healthy person is between 150,000 and 450,000 per microliter of blood. In this invention, 150,000 per microliter of blood is used as the threshold for thrombocytopenia.

[0093] In a preferred embodiment, the intravenous ticagrelor aqueous composition according to one embodiment of the present invention is administered to a patient with a platelet count of 50,000 to 150,000 per microliter of blood (thrombocytopenia). More preferably, the platelet count is 60,000 to 140,000 per microliter of blood, and even more preferably 70,000 to 130,000 per microliter of blood. The most preferred platelet count is 80,000 to 125,000 per microliter of blood.

[0094] Intravenous administration of ticagrelor may prevent the prolongation of thrombocytopenia caused by bacteremia and suppress the relative increase in platelet count. This may reduce mortality in patients with bacteremia.

[0095] Therefore, it is important to begin prevention in the early stages of bacterial infection, i.e., at the stage where platelet counts may decrease significantly. In preferred embodiments of the present invention, intravenous administration of ticagrelol is initiated within 4 days after bacterial bloodstream infection. Preferably, intravenous administration of ticagrelol is initiated 4, 3, 2, or 1 day after bacterial bloodstream infection. Since it can be difficult to determine the exact timing of infection, the diagnosis of bloodstream infection by Gram-positive bacteria can be used as a criterion for initiating ticagrelol administration. Bacterial bloodstream infection can be diagnosed by confirming the presence of bacteria in blood or blood culture samples.

[0096] Furthermore, it is beneficial to check the level of alpha-toxin produced by the relevant bacterial strain and adjust the ticagrelor dosage accordingly. High alpha-toxin levels can mitigate the effects of bacterial infection by occupying receptors targeted by alpha-toxin, such as the ADAM10 receptor targeted by Staphylococcus aureus alpha-toxin. Platelet protection may lead to improved clinical outcomes.

[0097] In preferred embodiments, the patient may also be administered an antibiotic selected from cefazolin, cephthaloline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, teravancin, trimethoprim-sulfamethoxazole, vancomycin, or a combination thereof. Adjunctive therapy with intravenous ticagrelol in combination with antibiotics is advantageous for providing a different mechanism of action against bacterial infections. Intravenous ticagrelol can be administered before, during, or in combination with the administration of one or more antibiotics. For intravenous administration, a small amount of ticagrelol aqueous solution, preferably 1-15 ml, may be added to the antibiotic infusion.

[0098] Preferably, treatment further includes an effective dose of platelets. Additional platelet administration may be beneficial, especially in situations where the platelet count is significantly reduced. Platelet replacement plays a role in replenishing platelets lost due to bacterial infection.

[0099] Pretreatment with ticagrelol is effective in maintaining the effectiveness of platelet replacement therapy. It is desirable to pretreatment platelets with ticagrelol before administering them to the patient. This prevents the effects of platelet replacement therapy from being short-lived and losing support for the immune system in fighting bloodstream infections.

[0100] Preferably, platelet replacement is performed by intravenous administration. Pretreatment with ticagrelol is achieved by infusing ticagrelol into the platelet solution before administration. Platelet pretreatment with ticagrelol has the advantage of rendering at least partially unavailable the receptors targeted by bacterial toxins, such as the ADAM10 receptor targeted by α-toxin in Staphylococcus aureus infections. This targeted (α) toxin-platelet interface interaction by ticagrelol may contribute to improved clinical outcomes in the treatment of bacteremia, particularly in staphylococcal bacteremia.

[0101] In preferred embodiments, the platelets used are prepared by lyophilization. It is advantageous to perform the lyophilization of platelets by the method disclosed in U.S. Patent No. US2021100846. The product is commercially available under the trade name Thrombosomes®. Lyophilized platelets are advantageous because they can be stored dry at room temperature for several years. They can be rehydrated with sterile water within minutes and immediately administered intravenously. In preferred embodiments of the present invention, ticagrelol-pretreated platelets for intravenous administration are obtained by reconstituting / rehydrating lyophilized platelets with an aqueous ticagrelol solution.

[0102] Preferably, the effective dose administered to the patient is less than 60 mg of ticagrelol per day. More preferably, the effective dose administered to the patient is less than 50 mg of ticagrelol per day, more preferably less than 40 mg, and most preferably less than 30 mg.

[0103] Ready-to-use ticagrelol intravenous solution In a further aspect, the present invention provides a ready-to-use aqueous solution for intravenous administration of ticagrelol, comprising a 5% glucose aqueous solution and a cyclodextrin-encapsulated ticagrelol complex containing 1 to 100 mg of ticagrelol and 2,000 to 3,000 mg of cyclodextrin, with the optional addition of a buffer and / or a tonicity modifier.

[0104] In this specification, "ready-to-use" means a product that does not require any compositional adjustments, such as changes in pH, osmotic pressure, volume, or ticagrelol concentration, before administration.

[0105] Preferably, a ready-to-use aqueous solution of ticagrelol according to one embodiment of the present invention has storage stability for at least 3 months at 25°C and 60% relative humidity.

[0106] Preferably, the ready-to-use ticagrelol composition of the present invention is provided for administering 20 to 65 mg of ticagrelol daily to bacteremia patients requiring ticagrelol. Administration may be once daily. More preferably, this ready-to-use ticagrelol composition is provided for administering 10 to 30 mg of ticagrelol.

[0107] The present invention further provides a method for producing a ready-to-use aqueous ticagrelol composition for intravenous administration in the treatment of bacteremia, according to one embodiment of the present invention. This method is as follows: 5-15 mg / ml of ticagrelol, 15-40% w / w hydroxypropyl-β-cyclodextrin, 5 mM to 20 mM phosphate buffer, Optional tonic modifiers, (Here, the pH is between 6.0 and 8.0) The process includes the steps of preparing an aqueous solution containing and diluting this ticagrelol aqueous solution with a 5% glucose aqueous solution to obtain a ready-to-use ticagrelol aqueous composition for intravenous administration.

[0108] Preferably, the above-mentioned ticagreol aqueous solution has a volume of 10 ml and is diluted in 25 ml of 5% glucose aqueous solution.

[0109] Packaging In a further embodiment, the present invention provides a container (packaging) containing a ticagrelol pharmaceutical composition according to one embodiment of the present invention. Preferably, the container is a plastic bag (infusion bag) or a glass bottle.

[0110] The present invention provides an infusion bag containing a ready-to-use ticagrelol solution according to one embodiment of the present invention.

[0111] The present invention further provides a ready-to-use container containing 25 to 1000 ml of aqueous solution, 0.10 to 14 mg / ml of ticagrelol, and 20 to 100 mg / ml of cyclodextrin (preferably hydroxypropyl-β-cyclodextrin). This container is intended for use in patients requiring treatment of Gram-positive bacteremia by intravenous administration of a therapeutically effective concentration of the pharmaceutical composition.

[0112] The present invention will be described below by the following non-limiting embodiments. [Examples]

[0113] Example 1 In Example 1, the solubilization of ticagrel was compared using two different cyclodextrins. Unbuffered stock solutions of HPβCD or SBECD were prepared in water at target concentrations of 20 w / w%, 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w%. Ticagrelol was slowly added under vortex stirring. The ticagrel concentration in milli-Q water was 5, 10, or 14 mg / ml. The ticagrel-cyclodextrin solutions were placed on a shaking table. No sonication or heating was performed.

[0114] The results in Tables 1 and 2 show that HPβCD can dissolve ticagrelol over a wider range of concentrations within the tested cyclodextrin and ticagrelol concentrations. Clear aqueous solutions were obtained by dissolving 5 mg / ml of ticagrelol in HPβCD at concentrations of 25 w / w%, 30 w / w%, 35 w / w%, and 40 w / w%.

[0115] In conclusion, ticagrelol could be dissolved by standing on a shaker. Sonication was not performed. HPβCD can be used at a ticagrelol concentration of 5 mg / ml using 40% w / w, 35% w / w, or 30% w / w cyclodextrin in Milli-Q water. These solutions remained clear while tested at room temperature for at least 3 days and at 4°C for several days.

[0116] [Table 1]

[0117] [Table 2]

[0118] Example 2 Following the experiment in Example 1, further optimization was performed by selecting an appropriate pH range to ensure the long-term stability of the ticagrelol-cyclodextrin inclusion aqueous solution. The compositions shown in Table 3 were prepared.

[0119] [Table 3]

[0120] HPβCD was dissolved in a buffer solution of pH 4.5, 5.5, or 6.5 prepared separately with water. After obtaining a clear solution, ticagrel was dissolved in the buffer solution while stirring for a certain period of time. The ticagrel in the buffer solution was filtered through a 0.22 micron filter and filled into USP Type I glass vials, which were then sealed and stored. All precautions were taken during manufacturing, including nitrogen purging and avoidance of direct sunlight. The vials were stored at 40°C and 75% relative humidity.

[0121] To confirm the stability of the formulation, each batch was evaluated using the related substance method by HPLC. The batch data is shown in Table 4 below.

[0122] Impurities in the formulation were analyzed using the gradient HPLC method with a YMC-Pack Pro C18 column (100 × 4.6 mm, S-3 μm, 12 nm). Good separation was obtained for all impurities.

[0123] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentan-1,2-diol. This is a degradable impurity related to the manufacturing process. Positional isomer impurity: (1S,2S,3R,5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentan-1,2-diol. This is a degradable impurity related to the manufacturing process. Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethane-1-ol. This is an impurity resulting from the manufacturing process. Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)cyclopentan-1,2,3-triol. This is an impurity resulting from the manufacturing process.

[0124] After 4 weeks under conditions of 40°C and 75% RH, it was observed that only the legiomeric impurities increased by approximately 0.3%. The specification value is 0.3%. Therefore, to further optimize the product stability, studies were conducted at pH 7-8.

[0125] Following the experiment in Example 1, an appropriate pH range was selected and further optimization was performed to ensure the long-term stability of the ticagrelor-cyclodextrin inclusion aqueous solution. The compositions shown in Table 3 were prepared.

[0126] [Table 3]

[0127] HPβCD was dissolved in a buffer solution of pH 4.5, 5.5, or 6.5 prepared separately with water. After obtaining a clear solution, ticagrel was dissolved in the buffer solution with constant stirring. The ticagrel in the buffer solution was filtered through a 0.22 micron filter and filled into USP Type I glass vials, which were then stored in a tightly sealed container. All precautions, such as nitrogen purging and avoidance of direct sunlight, were taken during preparation. The vials were stored at 40°C and 75% relative humidity.

[0128] To evaluate the stability of the formulation, each batch was assessed using the related substance method by HPLC. The batch data is shown in Table 4 below.

[0129] Impurities in the formulation were analyzed using the gradient HPLC method with a YMC-Pack Pro C18 column (100 × 4.6 mm, S-3 μm, 12 nm). Good separation was obtained for all impurities.

[0130] Amine impurity: (1S,2S,3R,5S)-3-(7-amino-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)-5-(2-hydroxyethoxy)cyclopentan-1,2-diol. This is a decomposition impurity resulting from the manufacturing process. Isomer impurities: (1S,2S,3R,5S)-3-((3-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-7-yl)amino)-5-(2-hydroxyethoxy)cyclopentan-1,2-diol. These are decomposition impurities related to the manufacturing process. Acetal impurity: 2-[[(3aR,4S,6S,6aS)-6-[7-[[1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo-[4,5-d]pyrimidine-3-yl]-2,2-dimethyltetrahydro-2H-3aHcyclopenta[d][1,3]dioxol-4-yl]oxy]ethane-1-ol. This is an impurity related to the manufacturing process. Triol impurity: (1S,2R,3S,4R)-4-(7-((1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-3-yl)cyclopentan-1,2,3-triol. This is an impurity resulting from the manufacturing process.

[0131] After 4 weeks under conditions of 40°C and 75% RH, only the legiomeric impurities were observed to increase by approximately 0.3%. The specification value is 0.3%. Therefore, to further optimize product stability, investigations were conducted at pH 7-8.

[0132] Example 3 Following the experiment in Example 2, a storage stability test was conducted at pH 7.5.

[0133] First, HPβCD was dissolved in a pH 7.5 phosphate buffer solution prepared separately with water. After obtaining a clear solution, ticagrelor was dissolved while constantly stirring. The solution was filtered through a 0.22 micrometer filter and filled into USP Type I amber glass vials. The vials were sealed and stored. All precautions were taken during manufacturing, including nitrogen purging and avoidance of direct sunlight.

[0134] [Table 4]

[0135] [Table 5]

[0136] [Table 6]

[0137] Based on the stability test results summarized in [Table 6], it was concluded that good storage stability was obtained under accelerated storage conditions of 40°C and 75% relative humidity. Legiomeric impurities were well controlled, and other impurities were not problematic.

[0138] Example 4 To optimize HPβCD concentrations below 40% w / w, further experiments involved heating at 40°C to promote the dissolution of the target ticagrelol dose at concentrations where obtaining a clear solution was difficult.

[0139] Table 7 shows the physical stability data obtained directly from the ticagrelol 5 mg / ml concentrate, as well as the physical stability data obtained from the agglutination test (dissolving 20 liters of sample in 1 mL of diluent). Table 7 also includes data on analytes, purity, osmotic pressure, and pH.

[0140] [Table 7]

[0141] Due to poor physical stability when diluted with physiological saline, a 32.5% w / w HPβCD was selected for the 5 mg / ml ticagrelor preparation. The stock solution was stable in the refrigerator even at a low HPβCD concentration of 22.5% w / w. At this concentration, a nearly isotonic preparation was obtained.

[0142] In conclusion, ticagrelor at a concentration of 5-15 mg / mL mixed with HPβCD in the 20-40% w / w range could be dissolved without heating. Even at low concentrations of HPβCD, such as 15-20% w / w, good solubility was obtained through heat treatment, yielding a clear solution.

[0143] To obtain a ticagrelor solution of a concentration suitable for injection or intravenous administration, at least 15% w / w HPβCD was required.

[0144] Example 5 The results obtained in Example 4 show that the concentration of the additive can be adjusted so that the resulting ticagrelor solution is hypertonic. The osmotic pressure and pH of multiple batches were measured. The solution was 19 mM phosphate buffer with a pH of 7.5. The results are shown in Table 8.

[0145] [Table 8]

[0146] Dilution tests were conducted to find the appropriate dilution.

[0147] Stability was evaluated for 5 mg / mL ticagrelor-cyclodextrin solutions containing various amounts of HPβCD, diluted with physiological saline, 5% glucose solution, or Ringer's lactate solution. The ticagrelor concentration was 0.1 mg / mL when diluted with glucose solution or physiological saline. The results are summarized in Table 9.

[0148] [Table 9]

[0149] Further screening was conducted to investigate the effects of buffer concentration on pH and osmotic pressure. The results are summarized in Table 10.

[0150] [Table 10]

[0151] It was concluded that a pH 7.5 phosphate buffer had little effect on osmotic pressure at various buffer concentrations, except for a buffer concentration of 0.19 mM. The pH of this buffer was altered because its strength was too weak.

[0152] Example 6 As yet another example, we tested the effect of particle size on solubility.

[0153] For the active ingredient ticagrelol, two particle sizes were selected: 5.5 micrometers and 15 micrometers. pH and osmotic pressure were not affected. As shown in [Table 11], the smaller the particle size, the shorter the dissolution time.

[0154] Micronization of Chikagreroll improves dissolution time. Therefore, micronized Chikagreroll with a D90 of less than 10 micrometers is desirable.

[0155] As used herein, the term "D90" means that at least 90% of the particles present are smaller than the target particle size. However, it is understood that there is variability in the particle size distribution (PSD) of the Chikagure roll, which affects the dissolution rate of the Chikagure roll.

[0156] [Table 11]

[0157] Example 7 To optimize the HPβCD concentration and pH of the intravenous administration solution, a 12-week / 3-month stability test was conducted. A composition was prepared by mixing 32.5% w / w HPβCD with 5 mg / mL ticagrelor at pH 7-8 and stored. Its stability was tested periodically.

[0158] The stability profiles at three different pH levels (7, 7.5, and 8) were compared as follows. In all three formulations, the manufacturing process was kept constant at a buffer concentration of 19 mM. The results are summarized in Tables 12 to 14.

[0159] [Table 12]

[0160] [Table 13]

[0161] [Table 14]

[0162] Based on the above data, it was concluded that the ticagrelor solution in HPβCD is stable in the pH range of 7-8.

[0163] Example 8 To investigate the potential influence of packaging materials on the stability of ticagrelor-cyclodextrin inclusion complexes, compositions containing 32.5% w / w HPβCD were prepared using the same procedures and precautions as in previous studies. Samples were placed in clear and amber glass vials and stored at 40°C / 75% RH. The results are shown in Tables 15 and 16.

[0164] The results of the accelerated storage stability test described above showed no significant difference between the two samples after 3 months. All samples remained clear aqueous solutions. The pH of the samples remained stable. No significant changes in impurities were observed.

[0165] Both clear and amber glass vials are considered usable.

[0166] Compared to the results of accelerated storage stability tests of ticagrelor solutions without cyclodextrin, it is clear that the use of cyclodextrin is important for achieving good stability. Without cyclodextrin, 6-8 types of impurities were generated during storage. These impurities were not observed in the selected composition.

[0167] [Table 15]

[0168] [Table 16]

[0169] From the above data, we surprisingly concluded that ticagrelor solution can be stabilized with HPβCD in both amber and clear glass vials.

[0170] Example 9 Further embodiments of the present invention are summarized in Table 17. To further improve the solubility of ticagrel, attempts were made to further improve the solubility of ticagrel by adding HPβCD at different concentrations, for example, 0% w / w. As a result, a solubility of ticagrel of 13 mg / ml was possible.

[0171] [Table 17]

[0172] The investigation confirmed that using HPβCD at a concentration of 20-40% w / w allows the concentration of the ticagrelol solution to be adjusted to 5-13 mg / ml. The filling volume can be adjusted according to the required dosage.

[0173] Surprisingly, it was found that the low-volume target dose of ticagrelol, 5-15 mg / ml, could be achieved by adjusting the proportion of HPβCD and the total volume of the injectable solution. Maintaining a ticagrelol dose in a volume of 5-15 ml is extremely important because it is a typical bolus injection volume.

[0174] Example 10 As another example, the maximum solubility of ticagrel in HPβCD solution without heat treatment was investigated. The results are summarized in [Table 18].

[0175] Depending on the amount of ticagrelol administered to the patient and the sample volume limited by injection or infusion, 2000 to 4000 mg of HPβCD per 10 mL vial is required to dissolve 65 to 75 mg of ticagrelol.

[0176] [Table 18]

[0177] Surprisingly, the solutions shown in [Table 18] were compatible with intravenous fluid diluents, particularly 5% glucose aqueous solution.

[0178] Example 11 In another embodiment of the present invention, by applying appropriate heating during preparation, a very stable and transparent solution of ticagrelol can be obtained, resulting in a completely transparent solution at the desired HPβCD and ticagrelol concentrations.

[0179] To investigate the effects of temperature and holding time, new compositions were prepared as shown in Table 19 below.

[0180] [Table 19]

[0181] In the first step, a pH 7.5 phosphate buffer was prepared and heated to 40°C-45°C. HPβCD was continuously added to this buffer while mixing. Once a clear solution was obtained, ticagrel was dispersed in the HPβCD solution and mixed until a clear solution was obtained. This usually took 30 minutes to 4 hours depending on the batch size. The solution was then filtered through a 0.22 micron filter and packed into appropriate clear or amber glass vials.

[0182] [Table 20]

[0183] [Table 21]

[0184] [Table 22]

[0185] Retention time studies at temperatures between 25°C and 45°C showed that ticagrelor could be stabilized even after prolonged heating of the solution and after maintaining the bulk at high temperatures, even with 30% w / w HPβCD.

[0186] A ready-to-use preparation Example 13 With the aim of preparing a ready-to-use aqueous ticagreol composition, several diluted ticagreol compositions were prepared and tested for solubility and stability.

[0187] [Table 24]

[0188] [Table 25]

[0189] [Table 26]

[0190] [Table 27]

[0191] [Table 28]

[0192] The composition of the present invention can be stored for at least 3 months at 25°C and 60% relative humidity.

[0193] Method for manufacturing ready-to-use intravenous fluid preparations The manufacturing process for the ready-to-use solutions exemplified above is as follows: In all cases, prepare the solvent, place it in a beaker, and heat it to 40°C. Next, add HPβCD and stir to obtain a clear solution. Then, add the active ingredient, ticagrelor, at 40°C and stir for a certain period of time until a clear solution is obtained. Filter this solution through a 0.22 micron filter and aseptically fill it into sterile glass bottles or infusion bags.

[0194] To obtain a stable ticagrelor infusion, HPβCD at a concentration of 24 mg / ml to 350 mg / ml was required. The amount of cyclodextrin needed depends on the volume of the infusion solution.

[0195] Ticagrelor is an active ingredient that is insoluble in water. The higher the concentration of ticagrelor in a diluted aqueous solution, the more likely it is to precipitate. As the dilution ratio of ticagrelor increases from 30 mL to 100 mL to 200 mL, the amount of cyclodextrin must also increase proportionally. However, for volumes of 650 mL or more, it was found that 16 g of cyclodextrin is sufficient to retain ticagrelor in the aqueous solution.

[0196] It is important to note that organic cosolvents, surfactants, and other solubilizers should not be used.

[0197] Alternative preparation method from ticagrelol concentrate Diluting 8 mL of ticagrelol (65 mg / vial) and approximately 3 g of HPβCD in 25 mL of 5 w / v% glucose solution yields a clear solution with a final volume of 33 mL.

[0198] However, this method was not possible when a 0.9 w / v% NaCl solution was used as the diluent for the ticagrelol concentrate.

[0199] This is important in medical applications where a concentrated ticagreol aqueous composition is mixed with other drugs. Specifically, ticagreol may precipitate, potentially rendering the combination unsuitable for intravenous administration.

[0200] Example 14 Ticagrerol aqueous solution for intravenous administration in the treatment of bacteremia

[0201] A ticagrelol aqueous solution for intravenous administration was prepared with the following composition: Ticagrelol 5-15 mg / ml HPβCD 20-40% w / w Amount to make 1 mL of acetate buffer or phosphate buffer with a pH of 4.5-6.5 Solution pH: 6~8 Osmotic pressure: 350-900 mOsm / kg Fill 5-15 mL of ticagrelol aqueous solution into glass vials and package them. Storage stability: More than 3 months at 40°C and 75% relative humidity.

[0202] The patient was diagnosed with MRSA bacteremia through a blood culture at the hospital.

[0203] Within four days of obtaining a positive test result, the patient will be administered ticagrelol 30 mg intravenously as an aqueous intravenous solution. This administration will be repeated twice daily for several days until bacteremia resolves.

[0204] Example 15 Ticagrelol aqueous solution for intravenous administration in the treatment of bacteremia and bacteremia-associated thrombocytopenia

[0205] Patients are diagnosed with MRSA bacteremia and bacteremia-associated thrombocytopenia based on blood cultures and platelet counts.

[0206] Patients should be administered intravenously in a therapeutically effective dose of the readily available ticagrelor aqueous composition shown in [Table 28] (which can be stored for at least 3 months at 25°C and 60% relative humidity). This administration should be repeated until bacteremia disappears and thrombocytopenia is resolved.

[0207] Example 16 Ticagrelol aqueous intravenous solution for the treatment of bacteremia

[0208] Human patients are diagnosed with Gram-positive bacteremia. Following diagnosis, the patient is intravenously administered a therapeutically effective dose of a readily available ticagrelol intravenous administration composition shown in [Table 28].

[0209] Example 17 Ticagrelol aqueous intravenous solution for the treatment of bacteremia-associated thrombocytopenia

[0210] Human patients are diagnosed with Gram-positive bacteremia. The patients' platelet counts are 80,000–120,000 per microliter of blood. A ticagrelol aqueous intravenous administration composition, which has storage stability for at least 3 months at 25°C and 60% relative humidity, was mixed with a platelet infusion bag. This mixture was administered intravenously to bacteremia patients at a therapeutically effective dose. Treatment was repeated until bacteremia resolved and the platelet count recovered to a level exceeding 150,000 per microliter.

Claims

1. A ticagrelol pharmaceutical composition for use in the treatment of patients requiring treatment for Gram-positive bacteremia by administering it at a therapeutically effective concentration, wherein the ticagrelol pharmaceutical composition is an aqueous solution of ticagrelol, has storage stability for at least 3 months at 25°C and 60% relative humidity or 40°C and 75% relative humidity, and is administered intravenously by injection or infusion.

2. The ticagrelol pharmaceutical composition according to claim 1, wherein the pH is 5.5 to 9.0 and the osmotic pressure is 300 to 900 mOsm / kg.

3. The ticagrelol pharmaceutical composition according to claim 1 or 2, wherein the cyclodextrin is preferably a water-soluble ticagrelol in hydroxypropyl-β-cyclodextrin.

4. A ticagrelol pharmaceutical composition according to any one of claims 1 to 3, which does not contain an organic cosolvent.

5. A ticagrelol pharmaceutical composition according to claims 1 to 4, comprising 1 to 15 mg / ml of ticagrelol and 15 to 40% w / w of cyclodextrin.

6. The ticagrelol pharmaceutical composition according to claim 5, having a volume of 1 to 15 ml for injection administration and a volume of 10 to 50 ml for short-term infusion administration over a maximum of 30 minutes.

7. A ticagrelol pharmaceutical composition according to claims 1 to 4, comprising 0.10 to 14 mg / ml of ticagrelol and 20 to 100 mg / ml of cyclodextrin.

8. The ticagrelor pharmaceutical composition according to claim 7, having a volume of 25 to 1000 ml for intravenous administration over at least 30 minutes.

9. The ticagrelor pharmaceutical composition according to any one of claims 1 to 8, wherein the Gram-positive bacteremia is caused by Staphylococcus, Streptococcus, or Enterococcus, preferably by Staphylococcus aureus, more preferably by antibiotic-resistant bacterial infection, and most preferably by methicillin-sensitive (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA).

10. The ticagrelor pharmaceutical composition according to any one of claims 1 to 9, wherein the patient is further administered an antibiotic selected from cefazolin, cephthaloline, daptomycin, ertapenem, linezolid, minocycline, oxacillin, teravancin, trimethoprim, sulfamethoxazole, vancomycin, or a combination thereof.

11. The ticagrelol pharmaceutical composition according to any one of claims 1 to 10, wherein intravenous administration of ticagrelol is initiated within four days of a bacterial bloodstream infection.

12. The ticagrelol pharmaceutical composition according to any one of claims 1 to 11, wherein the dose of ticagrelol is adjusted according to the level of alpha-toxin produced by Gram-positive bacterial strains present in bloodstream infections.

13. The ticagrelol pharmaceutical composition according to any one of claims 1 to 12, wherein the patient's platelet count is 50,000 to 150,000 per microliter (thrombocytopenia).

14. The ticagrelol pharmaceutical composition according to claim 13, further comprising administering an effective amount of platelets for the treatment of thrombocytopenia.

15. The ticagrelol pharmaceutical composition according to claim 14, wherein platelets are pretreated with ticagrelol.

16. A container comprising the ticagrelol pharmaceutical composition according to any one of claims 1 to 15.

17. The container according to claim 16, wherein the container is a plastic bag or a glass bottle.

18. A ready-to-use container for intravenous administration by drip infusion to patients requiring treatment for Gram-positive bacteremia, comprising a therapeutically effective concentration of a pharmaceutical composition containing 25 to 1000 ml of aqueous solution, 0.10 to 14 mg / ml of ticagrelol, and 20 to 100 mg / ml of cyclodextrin, preferably hydroxypropyl-β-cyclodextrin.

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